Setmelanotide (brand name Imcivree®) is a cyclic octapeptide derivative and the next-generation potent and selective melanocortin-4 receptor agonist. The melanocortin-4 receptor is an integral part of the central nervous system energy homeostasis regulation network.
Setmelanotide is similar in action to endogenous human melanocortins (such as α-melanocyte stimulating hormone, α-MSH), but has been developed to be vastly more potent, selective and metabolically stable than the natural ligand.
It shows very low EC50 (half-maximal effective concentrations) for both human and rat MC4R–0.27 nM and 0.28 nM respectively, thereby reflecting its high receptor activation potency.
Setmelanotide activates intracellular cAMP signaling through stimulation of melanocortin-4 receptors present in different parts of the brain, including the hypothalamus, and therefore regulates appetite, energy expenditure and autonomic nervous activity including modulation of blood pressure control by stimulating preganglionic neurons of the sympathetic nervous system.
Due to its superior receptor binding properties, it serves as a valuable tool for studies of MC4R-accessory proteins (e.g., MRAP2) interaction.
In clinical settings, Setmelanotide has been successfully translated into a therapeutic drug focused on treating rare genetic obesity syndromes derived from defects in the leptin-melanocortin pathway.
It also reverses drug-induced weight gain (e.g., risperidone), has anti-inflammatory effects in astrocytes, and may act synergistically with metabolic interventions such as caloric restriction—all of which demonstrates its high scientific value and potential applicability in other research fields (such as obesity, metabolic syndrome and neuroendocrine disorders).
Sequence
Ac-Arg-Cys-{d-Ala}-His-Phe-Arg-Trp-Cys-NH2 (Disulfide bridge:Cys2-Cys8)
CAS Number
920014-72-8
Molecular Formula
C₄₉H₆₈N₁₈O₉S₂
Molecular Weight
694.91
Research Of Setmelanotide
1.MC4R Pathway and the MOA of Setmelanotide
MC4R is a G protein-coupled receptor (GPCR) that is mainly expressed in the central nervous system, notably within a few nuclei of the hypothalamus.
These areas represent the core sites for sensing metabolic cues and controlling feeding behavior and energy balance.
In physiological conditions, this MC4R pathway participates in the inhibition of appetite and stimulation of energy expenditure.
This pathway is normally stimulated by α-melanocyte-stimulating hormone (α-MSH, a POMC derivative) produced by POMC neurons in the arcuate nucleus.
Activation of MC4R by α-MSH induces a cascade of downstream signals that suppress appetite and meal intake.
But if there are mutations in the POMC gene that prevent α-MSH synthesis, MC4R will remain “inactive” because it does not receive any activation by its endogenous ligands.
This signaling disruption results in pathological, uncontrolled appetite and subsequent morbid obesity.
Drug discovery for the MC4R pathway was notoriously difficult before Setmelanotide.
Early non-selective MC4R agonists elicited intolerable adverse effects such as skin pigmentation and sexual dysfunction by concomitantly stimulating other melanocortin receptors (i.e., MC1R, MC3R, and MC5R).
The development objective of Setmelanotide was straightforward: to achieve high selectivity for MC4R to optimize its effects in both appetite suppression and increased energy expenditure and minimize side effects related to off-target binding.
The inherent core mechanism of exogenous MC4R agonist Setmelanotide is to act as a substitute for α-MSH, directly stimulating the MC4R in order to correct pathophysiology upstream and restore this critical signal for energy balance.
The molecular and cellular effects of Setmelanotide ultimately translate into profound systemic physiological responses.
By stimulating MC4R neurons at important sites throughout the brain like the hypothalamus PVN, Setmelanotide is able to:
Obesity and Rare Genetic Obesity Syndromes Studies: Setmelanotide is an essential tool in studying the function of the MC4R pathway.
More notably, it has been shown to be effective in treating rare genetic forms of obesity due to deficiency in POMC, LEPR or PCSK1 and reverse serious early onset obesity from mutations in the MC4R pathway.
Setmelanotide acts to restore the function of energy balance regulation by activating the MC4R pathway, leading to substantial weight loss, decreased hunger, and improvement in metabolic parameters.
2.Regulation of Inflammation Function
Studies of Setmelanotide in astrocytes have shown that it serves a special anti-inflammatory function.
In pro-inflammatory cytokine (TNF-α/IFN-γ)–activated astrocytes, Setmelanotide can dramatically suppress the activation of NF-κB signaling pathway and decrease the secretion of pro-inflammatory chemokines (such as CCL2 and CXCL10).
Apart from inhibition of inflammation, Setmelanotide also induces astrocytes to secrete cytokines IL-6 and IL-11 that can promote macrophage polarization into an anti-inflammatory phenotype (M2 type).
3.Energy Expenditure Enhancement
In addition to directly reducing food intake (consumption), Setmelanotide also elevates resting energy expenditure (REE).
It’s like flipping on the body’s metabolic switch, enabling it to burn calories even at rest as if exercising.
Setmelanotide produced a large increase in basal metabolic rate (BMR) and active energy expenditure (AEA) , leading to rapid weight reduction in obese mouse models (e.g., the Magel2-null syndrome model).
The respiratory quotient (RER) decreases in animals after treatment, which indicates that the body switches from carbohydrate to fat oxidation, necessary for depleting liver and stored fat.
Resting energy expenditure (REE) was increased by 6.4% with Setmelanotide in a Phase III study on healthy obese subjects, during a relatively short treatment duration of 72 hours (111 kcal/24 h).
This means the patient’s body is burning extra calories, without any changes to diet.
4.Improved Metabolic Health
Setmelanotide not only induced weight loss but it also demonstrated reversal of obesity related metabolic diseases, including hepatic steatosis and insulin resistance.
Setmelanotide treatment not only reduced weight, but also reduced liver fat content, and hepatic damage.
This is not just an effect of weight loss but it’s a direct enhancement in liver function.
Concomitantly, patients’ fasting insulin levels markedly decreased with amelioration of insulin resistance, reflecting an improved state of glucose metabolism.
When fat mass declined, serum levels of leptin also fell.
This is generally believed to be an indicator of better metabolic health – since leptin levels that are too high often indicate obesity and insulin resistance.
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